PDBsum entry 4jsp

Transferase

PDB id: 4jsp

Contents

Protein chains

1058 a.a.

317 a.a.

Ligands

AGS ×2

Metals

_MG ×4

PDB id:

4jsp

Name:

Transferase

Title:

Structure of mtordeltan-mlst8-atpgammas-mg complex

Structure:

Serine/threonine-protein kinase mtor. Chain: b, a. Fragment: unp residues 1376-2549. Synonym: fk506-binding protein 12-rapamycin complex-associated protein 1, fkbp12-rapamycin complex-associated protein, mammalian target of rapamycin, mtor, mechanistic target of rapamycin, rapamycin and fkbp12 target 1, rapamycin target protein 1. Engineered: yes. Target of rapamycin complex subunit lst8.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: frap, frap1, frap2, mtor, raft1, rapt1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293. Gene: gbl, lst8, mlst8.

Resolution:

3.30Å R-factor: 0.234 R-free: 0.268

Authors:

N.P.Pavletich,H.Yang

Key ref:

H.Yang et al. (2013). mTOR kinase structure, mechanism and regulation. Nature, 497, 217-223. PubMed id: 23636326 DOI: 10.1038/nature12122

Date:

22-Mar-13 Release date: 01-May-13

Protein chains

P42345  (MTOR_HUMAN) -  Serine/threonine-protein kinase mTOR from Homo sapiens

Seq: 2549 a.a.

Struc: 1058 a.a.

Protein chains

Q9BVC4  (LST8_HUMAN) -  Target of rapamycin complex subunit LST8 from Homo sapiens

Seq: 326 a.a.

Struc: 317 a.a.

Enzyme reactions

• Enzyme class 1: Chains B, A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] (Bound ligand (Het Group name = AGS) matches with 93.75% similarity) + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)

L-threonyl-[protein] (Bound ligand (Het Group name = AGS) matches with 93.75% similarity) + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)

• Enzyme class 2: Chains D, C: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nature12122

Nature 497:217-223 (2013)

PubMed id: 23636326

mTOR kinase structure, mechanism and regulation.

H.Yang, D.G.Rudge, J.D.Koos, B.Vaidialingam, H.J.Yang, N.P.Pavletich.

ABSTRACT

The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.